The gene expression patterns as surrogate indices of pH in the brain

Hydrogen ion (H⁺) is one of the most potent intrinsic neuromodulators in the brain in terms of concentration. Changes in H⁺ concentration, expressed as pH, are thought to be associated with various biological processes, such as gene expression, in the brain. Accumulating evidence suggests that decreased brain pH is a common feature of several neuropsychiatric disorders, including schizophrenia, bipolar disorder, autism spectrum disorder, and Alzheimer's disease. However, it remains unclear whether gene expression patterns can be used as surrogates for pH changes in the brain. In this study, we performed meta-analyses using publicly available gene expression datasets to profile the expression patterns of pH-associated genes, whose expression levels were correlated with brain pH, in human patients and mouse models of major central nervous system (CNS) diseases, as well as in mouse cell-type datasets. Comprehensive analysis of 281 human datasets from 11 CNS disorders revealed that gene expression associated with decreased pH was over-represented in disorders including schizophrenia, bipolar disorder, autism spectrum disorders, Alzheimer's disease, Huntington's disease, Parkinson's disease, and brain tumors. Expression patterns of pH-associated genes in mouse models of neurodegenerative disease showed a common time course trend toward lower pH over time. Furthermore, cell type analysis identified astrocytes as the cell type with the most acidity-related gene expression, consistent with previous experimental measurements showing a lower intracellular pH in astrocytes than in neurons. These results suggest that the expression pattern of pH-associated genes may be a surrogate for the state- and trait-related changes in pH in brain cells. Altered expression of pH-associated genes may serve as a novel molecular mechanism for a more complete understanding of the transdiagnostic pathophysiology of neuropsychiatric and neurodegenerative disorders.